This proposal describes a series of synthetic studies on deazatetrahydrofolates, a new class of folate antimetabolites which inhibit de novo purine biosynthesis and have shown extraordinarily potent and selective antitumor activity. The lead compound in this series is 5,10- dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF), which we designed as an antifolate with a target other than dihydrofolate reductase, the site of classical antifolate action. DDATHF is now entering clinical trial. We plan to probe the structural requirements for antiproliferative activity by synthesizing a number of carefully selected analogs which differ from DDATHF in such features as the nature of the left-hand heterocyclic ring, deletion of the chiral center at C-6, and the nature, flexibility and dimensions of the middle bridge region. Of primary importance in our synthetic studies will be the development of chiral synthetic procedures in order to simplify the severe synthesis problems associated with the presence of multiple chiral centers in our target analogs.